Influenza viruses circulate in both avian and human hosts and account for annual outbreaks resulting in significant morbidity, mortality and the constant threat of a worldwide pandemic. The viruses'evolutionary success is largely credited to its capacity for evading host immunity. Viral pathogenicity itself is thought to result from the robust cellular response to infection that is rendered ineffective by the expression of virus- specific antagonistic proteins. Therefore, the success of future antiviral drug and vaccine design demands a thorough understanding of these host-pathogen interactions. Recently, an IKK-related kinase called IKK? was identified as a novel molecular determinant in the cellular response to influenza virus. Mice lacking this kinase were unable to inhibit virus replication and were thus rendered hypersusceptible to infection. These data suggest that this kinase, and the cellular pathway which it controls, serve as exciting new candidate antiviral targets. This proposal focuses on three interrelated aims to better characterize the role of IKK? and influenza virus-induced pathogenicity. The focus of Aim 1 is to identify the kinase responsible for IKK? activation following influenza-induced cytokine signaling. Aim 2 is to elucidate the function of IKK?-mediated phosphorylation of STAT1. Aim 3 is to characterize how the levels of IKK? modulate the cellular transcriptome following influenza virus infection. This proposal is thus designed to further elucidate the cellular response to influenza virus infection, to identify determinants of viral pathogenicity, and to discover novel components for use in antiviral drug and vaccine design. PUBLIC HEALTH RELEVANCE: Given the ever-present global burden of influenza virus, the study of host-virus interactions can result in discoveries that have immediate impact on human health. We have discovered that IKK?, a virus- and interferon-activated kinase, induces a cellular response that is critical in controlling influenza virus replication. This application focuses on understanding IKK?-mediated anti-viral signaling in order to identify novel targets for immune modulation and the treatment of influenza virus pathogenesis.